Proton extrusion during oxidative burst in microglia exacerbates pathological acidosis following traumatic brain injury

Rodney M. Ritzel, Junyun He, Yun Li, Tuoxin Cao, Niaz Khan, Bosung Shim, Boris Sabirzhanov, Taryn Aubrecht, Bogdan A. Stoica, Alan I. Faden, Long Jun Wu, Junfang Wu

Research output: Contribution to journalArticlepeer-review

Abstract

Acidosis is among the least studied secondary injury mechanisms associated with neurotrauma. Acute decreases in brain pH correlate with poor long-term outcome in patients with traumatic brain injury (TBI), however, the temporal dynamics and underlying mechanisms are unclear. As key drivers of neuroinflammation, we hypothesized that microglia directly regulate acidosis after TBI, and thereby, worsen neurological outcomes. Using a controlled cortical impact model in adult male mice we demonstrate that intracellular pH in microglia and extracellular pH surrounding the lesion site are significantly reduced for weeks after injury. Microglia proliferation and production of reactive oxygen species (ROS) were also increased during the first week, mirroring the increase in extracellular ROS levels seen around the lesion site. Microglia depletion by a colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622, markedly decreased extracellular acidosis, ROS production, and inflammation in the brain after injury. Mechanistically, we identified that the voltage-gated proton channel Hv1 promotes oxidative burst activity and acid extrusion in microglia. Compared to wildtype controls, microglia lacking Hv1 showed reduced ability to generate ROS and extrude protons. Importantly, Hv1-deficient mice exhibited reduced pathological acidosis and inflammation after TBI, leading to long-term neuroprotection and functional recovery. Our data therefore establish the microglial Hv1 proton channel as an important link that integrates inflammation and acidosis within the injury microenvironment during head injury.

Original languageEnglish (US)
JournalGlia
DOIs
StateAccepted/In press - 2020

Keywords

  • acidosis
  • chronic neurodegeneration
  • microglia
  • neuroinflammation
  • traumatic brain injury

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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